The present invention generally relates to methods for the treatment of a variety of diseases and disorders utilizing systemically-introduced nanoparticles to create focused hyperthermia of a target area so as to enhance the efficacy of additional therapies.
Radiation therapy is often a component of the multidisciplinary approach to the treatment of many tumors. However, as a single modality, radiation therapy is unable to eradicate all locoregional recurrences and/or cure localized cancers. This ineffectiveness is largely related to the intrinsic resistance of some cancer cells to ionizing radiation. Moeller, B. J.; Richardson, R. A.; Dewhirst, M., W. Cancer Metastasis Rev. 2007, 26, (2), 241-48.
Intratumoral hypoxia is believed to be a key mediator of this resistance to radiation therapy and is exacerbated by inadequate oxygenation via mutated, chaotic and incomplete blood vessels in tumors. McDonald, D. M.; Choyke, P. L. Nat Med 2003, 9, (6), 713-25; Baluk, P.; Morikawa, S.; Haskell, A.; Mancuso, M.; McDonald, D. M., Am J Pathol 2003, 163, (5), 1801-15. Hypoxia is known to induce the expression of a spectrum of genes involved in metabolism, proliferation, apoptosis, and angiogenesis. Harris, A. L., Nat Rev Cancer 2002, 2, (I), 38-47; Hockel, M.; Vaupel, P., J Natl Cancer Inst 2001, 93, (4), 266-76; These hypoxia-induced tumor cellular and microenvironmental changes contribute to tumor aggressiveness and resistance to radiation therapy. Zhang, Y.; Li, M.; Yao, Q.; Chen, C. Med Sci Monit 2007, 13, (10), RA 175-80. Consequently, any therapeutic strategy that alleviates tissue hypoxia could potentially overcome a major mechanism of radioresistance and enhance the effects of radiation therapy.
One such highly effective therapeutic adjunct to radiation therapy is mild temperature hyperthermia, which has direct anti-tumor effects and tumor microenvironment effects mediated, in part, through mitigation of hypoxia that contribute to the observed radio-insensitization. Roti Roti, J. L. Int J Hyperthermia 2004, 20, (2), 109-14; Kampinga, H. H.; Dikomey, E. Int J Radial Biol 2001, 77, (4), 399-408; Moros, E. G.; Corry, P. M.; Orton, C. G. Med Phys 2007, 34, (1), 1-4. Mild temperature hyperthermia mediates its anti-tumor effects via subtle influences on the tumor microenvironment, activation of immunological processes, induction of gene expression and induction of protein synthesis. While these effects do not independently cause tumor cell cytotoxicity, they lead to greater effectiveness of other conventional treatment modalities such as radiation therapy, chemotherapy and immunotherapy. In particular, in its role as an adjunct to radiation therapy, hyperthermia serves as a dose-modifying agent that increases the therapeutic ratio of radiation therapy, i.e. enhanced effectiveness without additional toxicity.
Various methods have been used to combine hyperthermia and radiotherapy. One example included applying interstitial radiation with interstitial hyperthermia in brain tumors. Another example used magnetic particles directly injected into a tumor and external beam radiation. Recently, iron oxide particles have been directly injected into a tumor and an alternating magnetic field applied for hyperthermia followed by ionizing radiation.
As another example, in U.S. Pat. No. 5,620,479, Diederich describes a method and apparatus for thermal therapy of tumors using piezoceramic tubular transducers for the delivery of interstitial thermal therapy in conjunction with simultaneous brachytherapy or radiotherapy from within the applicator. In yet another example, in U.S. Pat. No. 6,957,108, Turner et al. describe a microwave hyperthermia apparatus that can be inserted into the body that includes a hollow central tube for the insertion of radioactive therapy sources for hyperthermia and brachytherapy.
Several randomized trials have demonstrated improved response rates and survival when patients with locally advanced malignancies are treated with locoregional hyperthermia and radiotherapy compared to radiotherapy alone. Despite convincing evidence for hyperthermic radiosensitization, it is underutilized in routine clinical practice for the following reasons: (a) the invasive means of achieving and maintaining hyperthermia, (b) the time commitment involved in a treatment, which can often last about an hour, (c) the lack of good thermal dosimetry and (d) the inability to achieve localized hyperthermic temperatures. Thus, conventional methods for utilizing hyperthermia to enhance other treatment therapies suffer from a variety of disadvantages.
A localized dose enhancement of ionizing radiation can also result from the presence of certain elements in the tumor. For example, in U.S. Pat. No. 7,367,934. Hainfeld et al. describe the use of heavy metal particles delivered to a tissue or cells to achieve a concentration within the tissue of at least 0.1% metal by weight, applying ionizing radiation of specified energy and achieving a localized radiation dose enhancement. The radiation enhancement achieved from the interaction of the metal and the radiation, requiring a minimum metal content for efficacy.
As an alternative approach to cancer therapy, vascular disruptive agents (“VIDA”) are being developed in an attempt to treat cancer through the elimination or disruption of the blood supply. These agents may also be used in conjunction with ionizing radiation. Vascular disruption of a single established blood vessel, be it via subtle structural changes of dysmorphic endothelial cells or induction of intravascular coagulation, could potentially eliminate hundreds or thousands of tumor cells downstream. Vascular disrupting agents in preclinical and early clinical development include combretastatin A4 phosphate (CA4P), ZD6126, TZT-1027, AVE8062, ABT-751, and MN-029, which target the tubulin cytoskeletal network of endothelial cells; 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which targets autocrine endothelial regulatory cascades; and exherin (AFH-1), which targets cell adhesion. While these agents have shown promise in early trials, there is concern that more than just tumor vessels may be targeted by systemic exposure to these agents. In particular, damage to vascular compartments outside the tumor may contribute to acute coronary syndromes and thromboembolic events. Consequently, conventional treatment methods lack the ability to focus such treatments on specific target areas.
While a principal use of ionizing radiation is in the treatment of cancer, other diseases and disorders may benefit from radiotherapy if the ionizing effects could be confined to the target area or, alternatively, if the target area could be sensitized to the effects of ionizing radiation by a non-invasive method. For example, there are other medical conditions in which disruption of the vasculature is desired, such as arteriovenous malformations (AVMs), which can result in hemorrhage or other deleterious effects depending on their location (in case of brain AVMs, seizures and aberrant vascular perfusion of adjacent normal brain).
Accordingly, improved treatment methods are needed to address one or more of the disadvantages of the prior art.